SMARCA4 regulates the NK-mediated killing of senescent cells

Sci Adv. 2025 Jan 17;11(3):eadn2811. doi: 10.1126/sciadv.adn2811. Epub 2025 Jan 15.

Abstract

Induction of senescence by chemotherapeutic agents arrests cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the NK-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells. We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the SASP via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian cancer.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cellular Senescence* / drug effects
  • DNA Helicases* / genetics
  • DNA Helicases* / metabolism
  • Female
  • Humans
  • Killer Cells, Natural* / drug effects
  • Killer Cells, Natural* / immunology
  • Killer Cells, Natural* / metabolism
  • Mice
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Signal Transduction / drug effects
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism

Substances

  • SMARCA4 protein, human
  • Transcription Factors
  • DNA Helicases
  • Nuclear Proteins